This laboratory has been investigating the genetic and biochemical changes associated with drug resistance in human breast cancer cells as well as studies on the cell cycle regulation of human mammary epithelial cells. We have identified a number of changes associated with the development of multi-drug resistance including overexpression of the mdr1/P-glycoprotein drug efflux pump as well as changes in the number of drug metabolizing enzymes including glutathione transferase and the selenium dependent glutathione peroxidase gene. We have initiated studies on the role of these genes in development of resistance as well as on the regulation of expression of these genes in sensitive and drug resistant breast cancer cells. We have analyzed the transcription and posttranscriptions control mechanisms involved in the regulation of expression of the human mdr1 gene, the human pi class glutathione transferase gene, and the human selenium dependent glutathione peroxidase one gene. Other studies from our laboratory have identified other models of drug resistance. These include two models of non-P-glycoprotein associated with multidrug resistance. One of these is a mitoxantrone resistant breast cancer cell line with efflux in drug accumulation not associated with P-glycoprotein expression. The other is an etoposide resistant breast cancer cell line in which resistance is associated with non-P-glycoprotein associated decreases in drug uptake and alterations in toposomerase II activity. We also have studied a methotrexate resistant cell line that is defective in the reduced folate transport system. Additional studies in our laboratory have examined the cell cycle regulation of normal human mammary epithelial cells in comparison with estrogen receptor positive and estrogen receptor negative breast cancer cells.